Alterations in gene regulation play a key role in the tumorigenic process. Our research centers on two tumor[unreadable] suppressor pathways, p16lnk4a-cycD/cdk4-pRB-E2F and p19Art-mdm2-p53, that control the expression of[unreadable] genes required for cellular proliferation or the tumor surveillance response respectively. We have[unreadable] established a direct link between the pRB/E2F and An7p53 pathways in vivo (Aslanian et al., 2004): specific[unreadable] E2F family members contribute to either the transcriptional repression of Arf in normal cells (via E2F3B) or[unreadable] the transcriptional activation of /A/fin tumor cells (via the activating E2Fs). Experiments in this proposal will[unreadable] use a combination of mouse models (and the resulting cell lines and tumors) and RNAi technology to[unreadable] understand the role of the pRB/E2F pathway in the control of Arf transcription and cellular proliferation. They[unreadable] will also establish how the pRB pathway and cellular transformation influence miRNA regulation and[unreadable] function. There are four goals: (1) To identify the E2F3B represser complex; (2) To understand how the[unreadable] activating E2Fs induce Arf and other "tumor-specific" E2F-responsive genes; (3) To test the requirement for[unreadable] activating E2Fs in the regulation of normal and tumor cells; and (4) To screen for pathways that synergize[unreadable] with pRB in the control of cell proliferation and survival.